Process for production of gabapentin intermediate

ABSTRACT

The invention relates to a novel process for producing a the intermediary compound α,α′,dicyano-β,β-pentamethyleneglutarimide. The process includes the steps of reacting a ketone such as cyclohexanone with ethylcyanoacetate in the presence of ammonium hydroxide.

This application is a divisional application of U.S. application Ser.No. 09/984,058 filed Oct. 26, 2001 now U.S. Pat. No. 6,613,904, andclaims the filing date priority of U.S. Provisional Application No.60/244,891 filed Nov. 2, 2000.

FIELD OF THE INVENTION

The present invention relates to a compound that is used as anintermediate in the production of gabapentin, and a process forproduction thereof. More particularly, the present invention relates toα,α′,dicyano-β,β-pentamethyleneglutarimide, and a process formanufacturing α,α′,dicyano-β,β-pentamethyleneglutarimide.

BACKGROUND OF THE INVENTION

Gabapentin, 1-(aminomethyl)-1-cyclohexaneacetic acid, has the chemicalstructure of formula II:

Gabapentin is used for treating cerebral diseases such as epilepsy,faintness attacks, hypokinesis and cranial traumas. U.S. Pat. No.4,024,175 to Satzinger et al., incorporated herein by reference,discloses that gabapentin of formula (II) shows hypothermal and, in somecases, narcosis-potentiating or sedating properties as well asprotective effect against cardiozole cramp in animals. Gabapentin is theactive ingredient in Neurontin, marketed by Warner Lambert, and approvedby the Food and Drug Administration as an anti-epileptic, anti-seizure,or anti-convulsant medication. As such, there has been a need forproducing pure and stable gabapentin.

In one process for the preparation of gabapentin, an intermediary,α,α′,dicyano-β,β-pentamethyleneglutarimide (formula I)

is produced by the Guareschi reaction in the following manner.Cyclohexanone and ethylcyanoacetate are reacted in an anhydrousenvironment in the presence of gaseous ammonia dissolved in ethanol. Thereaction is represented as

The Guareschi reaction is inefficient as the reaction requires at least48 hours to proceed to completion, and more typically between 48-168hours for completion. In addition, current environmental regulationsmake it impractical to produce gaseous NH₃ in ethanol on a large scale.

SUMMARY OF THE INVENTION

The present invention relates to a process for producingα,α′,dicyano-β,β-pentamethyleneglutarimide (formula I) by reactingcyclohexanone and ethylcyanoacetate in the presence of ammoniumhydroxide. The process of the present invention can be substantiallycompleted in less than 24 hours. The reaction of the present inventioncan be processed in an aqueous environment and may include at least onesolvent. The solvent can be methanol, ethanol or any similar solvent nothaving adverse affect on the reaction. Most importantly, a reaction ofthe present invention need not be conducted in an anhydrous environment.

DETAILED DESCRIPTION

We have discovered that contrary to previous practice in the art, theGuareschi reaction may be performed in the presence of water.Consequently, gaseous NH₃ can be replaced in the reaction ofα,α′,dicyano-β,β-pentamethyleneglutarimide by, for example, an aqueoussolution of ammonium hydroxide. Such aqueous solutions are significantlyeasier to handle since they avoid many of the environmental concernsthat would arise from handling gaseous NH₃ in ethanol.

Accordingly, in one embodiment of the invention a ketone is condensedwith ethylcyanoacetate in the presence of ammonium hydroxide. In anotherembodiment of the invention, the ketone is cyclohexanone.

A reaction according to the present invention is substantially completein less than 36 to 48 hours. In one embodiment of the invention, thereaction process is substantially completed in 24 to 36 hours. In apreferred embodiment, a reaction according to the present invention issubstantially completed in less than 24 hours.

In one embodiment of the present invention, a molar ratio ofethylcyanoacetate:ketone is in the range of 1:0.5 to 4:2. In a preferredembodiment of the present invention, a molar ratio ofethylcyanoacetate:cyclohexanone is 2:1.

The organic solvent used in the Guareschi reaction can be an alcohol oranother polar solvent. In a preferred embodiment the solvents are bemethanol and ethanol. In addition, esters of cyanoacetate acid, such asfor example, methylcyanoacetate can be used to replace ethylcyanoacetatein the Guareschi reaction.

The embodiments of the present invention are further described in thefollowing example.

EXAMPLE 1

In a three-necked round flask equipped with a reflux condenser, athermometer and an agitator 264.4 gm of ethylcyanoacetate and 312 gm ofmethanol are added. The solution is cooled to 8° C. while stirring. Twograms of ammonium acetate and 76.4 g or 1 equivalent versus 3equivalents of ethylcyanoacetate are added at 8° C. 60 g of ammoniumhydroxide solution 25% is added during 1 hour. During the addition ofammonium hydroxide, the temperature of the reaction mixture ismaintained between 8 to 11° C. The solution is further maintained forhalf an hour at 8-11° C. The cooling is stopped and the temperature ofthe reaction mixture is allowed to rise during 45 minutes to 25° C. Thesuspension is maintained for 20 hours at 25° C. After 20 hours, thesuspension is lightly heated and 50% sulfuric acid is added until the pHis 2. During the acidification the temperature is maintained in therange of 50-55° C. The reaction mass is cooled to 12° C. At 12° C. thesuspension is mixed for half an hour and then filtered. The filter cakeis washed with a mixture of methanol water (1:1 by weight). The mixtureis then washed with water.

After drying, 163 gm of α,α′,dicyano-β,β-pentamethyleneglutarimide(formula I) is obtained with an assay of 94% and a purity of 99.9%. Thisrepresents a yield of 85%.

1. A method of synthesizing pentamethylene glutarimides comprising:reacting a ketone and ethylcyanoacetate under the reaction conditions ofthe Guareschi reaction in the presence of water and ammonium hydroxidefor a time less than 36 to 48 hours.
 2. The method according to claim 1,wherein the reaction conditions of the Guareschi reaction comprise asuitable temperature.
 3. The method according to claim 1, wherein theketone is cyclohexanone.
 4. The method according to claim 1, wherein thesuitable time is from 24 hours to 36 hours.
 5. The method according toclaim 1, wherein the suitable amount of time is less than 24 hours. 6.The method according to claim 1, wherein the molar ratio ofethylcyanoacetate to ketone is in the range of 1:2.
 7. The methodaccording to claim 1, wherein the reaction solvent is methanol orethanol.
 8. The method according to claim 2, wherein the temperaturecomprises an addition temperature and a reaction temperature.
 9. Themethod according to claim 8, wherein the addition temperature is 8° C.to 10° C.
 10. The method according to claim 8, wherein the reactiontemperature is 25° C.